VKHD

1. Vogt Koyanagi Harada syndrome –
current perspectives
Clinical Ophthalmology 2016:10 2345–2361
Abeir Baltmr1 Sue Lightman1,2 Oren Tomkins-netzer1–3
1Uveitis Service, Moorfields Eye Hospital, London, UK; 2Department Of Clinical Ophthalmology, UCL Institute
Of Ophthalmology, London, UK; 3Faculty Of Medicine, Technion, Israel Institute Of Technology, Haifa, Israel
DR. AMEY TAMHANE

2. • Vogt–Koyanagi–Harada disease (VKHD) is a sight-threatening disease and a common cause of non infectious panuveitis.
It is described as a multisystemic, granulomatous inflammation related to T-cell-mediated autoimmune dysregulation,
targeting melanocytic self-antigens.
• The disease has a predilection for affecting melanocyte-containing tissues in the eye, the central nervous system (CNS),
the inner ear and the skin, appears in genetically susceptible individuals and is related to HLA-DRB1*0405.
• During the early acute phase of the disease, the inflammation is characterized by non-necrotizing diffuse granulomas,
which persist following recurrences (chronic recurrent phase).
• As the disease progresses, it undergoes a chronic convalescent phase, which is characterized by a non-granulomatous
inflammation, with later involvement of the choriocapillaris in the chronic recurrent phase
• The disease has a variable clinical presentation, and clinical diagnosis is aided by the help of ophthalmic imaging such as
fundus fluorescein angiography (FFA), indocyanine green angiography (ICG), and optical coherence tomography (OCT).
INTRODUCTION

3. HISTORICALASPECTS AND EPIDEMIOLOGY
• In 1906, Vogt reported a case of a 16-year-old patient with iridocyclitis and poliosis. In 1929, Yoshizo Koyanagi
described 16 cases with similar features, including six new cases.
• In addition to the anterior uveitis and extraocular manifestations described by Vogt and Koyanagi, Harada described in
1926 a primarily posterior uveitis with exudative retinal detachments and pleocytosis of cerebrospinal fluid (CSF): an
abnormal increase in the amount of lymphocytes and monocytes with normal glucose, as well as the prodromal phase of
the disease and the integumentary signs.
• These findings were later noted by Babel, Bruno, and McPherson to represent a single, progressive syndrome, and the
name was combined into VKHD syndrome.
• It appears to be more prevalent in people with Asian, Hispanic, Indian, Native American, or Mediterranean origin,
accounting for 7%–22.4% of uveitis referrals.
• VKHD commonly affects young females between 20 and 50 years of age, at a ratio of 2:1 in most large series. However,
paediatric cases, elderly onset and equal sex predilection have been reported in some studies.

4. CLASSIFICATION AND CLINICAL FEATURES
• VKHD is defined as a non-traumatic bilateral panuveitis and is associated with integumentary, neurological/auditory
signs. Probable (ocular) VKHD is characterized as matching ocular manifestations but in the absence of extraocular
manifestations.
• In all forms of the disease, there should be no history of ocular surgery and no clinical or laboratory evidence suggestive
of other ocular diseases.
• VKHD is a multiphasic disease that classically has four clinical phases or stages with variable clinical features in
different ethnic groups:
1) prodromal
2) acute
3) chronic convalescent
4) chronic recurrent stage

5. • The prodromal phase, which may mimic a viral infection, generally precedes the ocular inflammation by a few days
and lasts for 1–2 weeks.
• Patients typically complain of CNS and auditory symptoms including headaches, neck stiffness, photophobia, fever,
orbital pain, scalp or skin sensitivity, and focal neurological deficits such as cranial nerve palsies.
• May also have hearing loss, particularly for higher frequencies, dysacousia, vertigo, and tinnitus with less frequent
auditory features observed in Hispanic patients.
• CSF samples from lumbar punctures show pleocytosis in 80% of cases and brain imaging studies can occasionally
demonstrate focal parenchymal lesions.
PRODORMAL PHASE

6. ACUTE PHASE
• The acute phase of VKHD is characterized by a panuveitis or posterior uveitis with multifocal serous retinal detachments (SRDs).
• The diffuse choroidal thickening seen on OCT scans during the acute phase of VKHD correlates with diffuse mononuclear
inflammatory cellular infiltration of the uvea with sparing of the choriocapillaris and the appearance of Dalen-Fuchs nodules on
histopathological studies.
• The inflammation lasts several weeks, and early treatment may prevent the later development of the chronic phases of the disease in
up to a third of cases.
• However, progression to the chronic convalescence phase occurs in 28%–62% of patients who present with acute VKHD, possibly
due to more severe and rapid disease onset.
A) Multifocal choroiditis lesions of variable size representing along the
superior arcade (black arrow).
B) The posterior pole depicting a hyperemic optic disc (white arrow),
multifocal choroiditis (black arrow),and multiple areas of SRDs (red
arrows).
Swollen and hyperemic optic discs (white arrows), with choroidal folds
disc (black arrows), in the acute phase of VKHD.

7. CHRONIC CONVALESCENT PHASE
• The chronic convalescence phase usually develops 3–4 months after the onset of the disease and lasts from several weeks to years.
• Patients usually present with non-granulomatous panuveitis, poliosis of the eyebrows and eyelashes, vitiligo, and alopecia, as well as
depigmentation of the choroid resulting in a bright-orange hue.
• The optic nerve remains pale, leading to the appearance of sunset glow fundus.
• Despite early high-dose corticosteroid treatment, progression to the chronic recurrent phase may occur in up to 79% of the total cases
who presented with acute VKHD.
Sunset glow fundus with pale optic discs (white arrows) and bright-orange choroids (black arrows).
Note the peripapillary atrophy (grey arrow) and macular scaring (blue arrow)
Sunset glow fundus with a numerous small
choroidal depigmented atrophic lesions (black
arrow) and hyperpigmented lesions (white arrow)
in the retinal periphery.

8. • During the chronic recurrent phase, patients present with recurrent granulomatous anterior uveitis , and choroidal
thickening develops.
• Approximately 25% of VKHD patients develop posterior and anterior segment recurrences, mainly in cases of more
aggressive disease with poor response to immunosuppressive treatment.
• Anterior segment recurrences were found to be associated with choroidal inflammation and insufficient choroidal
circulation demonstrated on ICG and OCT scans.
CHRONIC RECURRENT PHASE
Chronic recurrent phase of the VKHD showing acute anterior uveitis and mild poliosis (white arrow).

9. OCULAR FINDINGS IN VKHD
Panuveitis
Multifocal choroiditis progressing to serous retinal detachments
Optic disc involvement
Choroidal folds – poor VA at presentation & poor visual outcome
Scleral involvement – bilateral posterior scleritis
Angle closure glaucoma
RPE tears bilaterally
VMT
Perilimbal vitiligo (Sugiura’s sign) – suggest ongoing uveal inflammation

10. IMAGING IN VKHD - FFA
Color retinal and FFA photographs of a patient in the acute phase of VKHD showing (A) hyperemic optic disc with deep yellow lesions of
variable size and multiple SRD, (B) early FFA showing delayed choroidal filling, (C) mid phase of FFA showing pinpoint hyperfluorescent
leakage at the RPE level (D) with pooling of the dye in the subretinal space in the late phase of the angiogram.

11. A hot disc can be observed in up to 94.4% of patients with acute VKHD and 66.6% of those in the chronic convalescent phase
Color retinal photograph of the right eye showing swollen and hyperemic optic discs (A) and FFA showing hot
disc (B) (white arrows), in the acute phase of VKHD.
IMAGING IN VKHD - FFA

12. Numerous hyperfluorescent pinpoint foci of leakage at the level of RPE result in a classic “starry sky” appearance on the FFA that is
highly suggestive of VKHD
IMAGING IN VKHD - FFA
FFA is also found to have a prognostic value in acute VKHD, where the absence of early pinpoint peripapillary hyperfluorescence on
pretreatment FFA is a poor prognostic factor for developing chronic VKHD, and its presence is observed in up to 85% of eyes that resolved.

13. In VKHD, ICG is used to confirm the presence of choroidal inflammation, monitor choroidal activity and response to therapy
IMAGING IN VKHD - ICGA
ICG photographs of the right eye of a patient in the acute phase of VKHD showing (A) patchy hypofluorescence during the early
angiographic phase, (B) large choroidal stromal vessel hyperfluorescence with fuzzy choroidal vessels in the early phase, (C)
hypofluorescent dark dots during the intermediate phase of angiography, and (D) diffuse choroidal hyperfluorescence in the late
phase.

14. IMAGING IN VKHD – B-SCAN ULTRASOUND
• Diffuse low-to-medium reflective choroidal thickening and SRD are evident during acute VKHD, especially when the SRD is too
extensive.
• Swollen ciliary body with shallow anterior chamber, vitreous condensations, and scleral or episcleral thickening have also been seen
on US in the acute stage.
• Subretinal fibrosis in chronic VKHD was described on US in 64.8% of the eyes with chronic VKHD as dome shaped, heterogeneous
lesion; however, no other clinical signs of the chronic disease were detected on the US.
• Therefore, it is relatively unreliable in detecting subclinical recurrences and minor changes in choroidal thick- ness due to its limited
resolution in comparison to OCT

15. IMAGING IN VKHD – FUNDUS AUTOFLUORESCENCE
Short wavelength light (blue) FAF photographs of eyes of a patient with chronic VKHD. (A) Right eye showing areas of hypo
autofluorescence (black arrow) corresponding to RPE atrophy and loss. (B) Left eye showing areas of hyper autofluorescence (white arrow)
corresponding to RPE proliferation.

16. IMAGING IN VKHD – OCT
OCT scan of the macula of a patient in the acute phase of VKHD before and after starting corticosteroid treatment.
(A) SRD (white arrow) and a mild fluctuation in the ILM (red arrow). (B) Resolution of SRD with treatment (white arrow).

17. TREATMENT
• The goal of treatment in VKHD is to suppress active ocular inflammation, prevent disease relapse and avoid sight- threatening
complications.
• Multiple therapeutic regimens are used combining both systemic immunosuppression agents together with locally administered
corticosteroids and anti- vascular endothelial growth factor drugs (anti-VEGF).
• Oral prednisone at a dose of 1–2 mg/kg/day started early in the course of the disease followed by slow tapering to avoid recurrences is
the generally accepted regimen, while pulse intravenous corticosteroid therapy of 1 g/day of methylprednisolone for 3–5 days followed
by oral prednisolone is usually reserved for cases with severe inflammation.
• Slow tapering of the corticosteroid dose, with frequent follow-up examinations, is warranted in order to avoid recurrence of posterior
segment inflammation.
• Aiming to reach a dose of ,7.5 mg/day over several months and keeping patients on long-term treatment may reduce the risk of
relapses, but nonetheless, these occur even when inflammatory control is achieved at high doses.
• Treatment at these low, safe doses with no evident ocular inflammation should be maintained for several years before cessation of
therapy is considered.

18. • Topical corticosteroids and cycloplegic agents are effective in controlling the anterior segment inflammation.
• The addition of second- line immunosuppressive agents including mycophenolate mofetil, methotrexate, cyclosporine, or
azathioprine are usually considered in patients who are not controlled with corticosteroids alone or cannot be tapered to a safe low
dose for the extended period of time they require to control their inflammation
• Use of these agents has been found to shorten the duration of the acute stage and to reduce the risk of progression to the chronic
stages and development of sight-threatening complications
• While intravitreal and posterior subtenon triamcinolone acetonide injections have been found to be effective in short-term control of
inflammation during the acute phase of VKHD, intravenous infusion of anti-tumor necrosis factor α agents (adalimumab and
infliximab) and rituximab, which is an anti-CD20 monoclonal antibody, has been used in refractory cases and found to be effective in
long-term disease control.
• Intravitreal injections of anti-VEGF have been used successfully for the treatment of CNVs,155 and combined treatment of
triamcinolone acetate and anti-VEGF has also been tried to treat recurrent CNVs
TREATMENT

19. • Glaucoma
• Cataract
• CNVM
• Subretinal fibrosis
• CME
• Band keratopathy
• Pseudotumoral RPE proliferation
• Posterior synechiae
• RRD and ERM
• MH and ERM
COMPLICATIONS ASSOCIATED WITH VKHD

20. CONCLUSION
• VKHD is a multisystemic autoimmune disease affecting mainly middle-aged patients; it has four distinct phases that may not
present in sequential order and detection of subclinical inflammation is still a challenge.
• Utilizing ocular imaging for diagnosis and repeat use of noninvasive modalities, such as OCT to monitor disease activity, can
promote early treatment and prevent the development of ocular complications.
• Early aggressive treatment with systemic corticosteroids during the acute stage is highly recommended.
• The use of immunosuppressive agents has reduced the risk of developing ocular complications; however, a considerable number
of patients still progress to the chronic stages, suffer recurrences and progress to visual loss, probably due to undetectable and
undertreated subclinical inflammation.